The use of disposable medical devices derived from synthetic and natural polymers has grown in recent years. These devices include monitoring tubes, artificial organs, catheters, blood filters, oxygenators, tubing sets and other devices that come into direct contact with blood during surgical or other medical treatment procedures. Recently, certain synthetic plastics have come into common use due to their desirable properties. These plastic materials have increased the ease of device manufacturing and are frequently the preferred materials for certain applications in prosthetic device technology.
One common property shared by all medical grade plastics is the possibility of the formation of thrombus on the surface when the plastic comes into direct contact with blood. The formation of thrombus or a clot creates the possibility of a number of serious complications. These include blood flow stoppage, pulmonary embolism, cerebral thrombosis or myocardial infarction. Traditionally, clinicians decrease the risk of thrombus by the administration of anticoagulants such as heparin, coumadin or other pharmacological agents. However, administration of these anticoagulants can be undesirable in some instances, because the anticoagulants may give rise to bleeding complications and because their anticoagulant effects are not easily reversed should bleeding complications such as gastrointestinal bleeding, occur.
Heparin is one well known systemic anticoagulant. This sulfated amino glycan polysaccharide of variable molecular weight is known to increase the inactivation rate of serum proteases such as thrombin and Factor Xa in conjunction with the inhibitor antithrombin III. Consequently, in the presence of heparin, the blood is less likely to form a thrombus and thereby avoid serious life threatening sequela. A review of the clinical biochemistry of heparin and its anticoagulation effects can be found in HEPARIN: CHEMICAL AND BIOLOGICAL PROPERTIES, CLINICAL APPLICATIONS (1989) edited by D. Lane et al., CRC Press, Inc., Boca Raton, Fla.
Due to the side effects resulting from direct systemic administration of sodium heparin, some researchers have sought to develop means for coating heparin onto those surfaces of medical devices that are intended to come into direct contact with blood. One example of a heparin coating is proposed in V. Gott, Science 142:1297 (1993). Gott proposes a coating for a graphite plastic surface which involves the cationic surfactant, benzalkonium chloride, complexed to the polyanion heparin. This ionic complex of cationic surfactant and heparin adheres to the surface of the plastic by virtue of the hydrophobic nature of the surfactant molecule and its attraction for the graphite surface.
Other approaches for coating heparin on a surface were proposed in U.S. Pat. Nos. 3,810,781 and 4,118,485 which relate to the treatment of heparin-coated surfaces with dialdehyde in order to crosslink the heparin molecules. U.S. Pat. No. 4,265,927 proposes treating a charged surface with heparin by contacting the surface with a colloidal aqueous solution of a complex compound of heparin and a cationic surfactant. The use of the dialdehyde purportedly affords a more stabilized heparin coating. However, the crosslinking that occurs in the heparin results in a decrease in the anti-thrombogenic activity of the heparin. The decrease in anti-thrombogenic activity observed by crosslinked heparin coatings is a common result of attempts to chemically modify heparin.
A number of heparin coatings based upon the formation of an ionic complex with sodium heparin or a heparin derivative are commercially available. Examples of such coatings include BENZALKONIUM HEPARIN.RTM. from Polyscience, Inc, TDMAC.RTM. heparin from Polyscience, Inc., and DUROFLOW II.RTM. from Baxter Biocompatible Technologies. These coatings are subject to leaching of the heparin due to the ionic nature of blood plasma. More specifically, heparin is lost from the surface as the cationic surfactant exchanges for other counterions present in the blood, such as sodium, potassium, and others.
Other heparin coatings have been developed which utilize alkylammonium salts as the cationic portion of the complex. For example, U.S. Pat. No. 4,046,725 proposes a polyurethane copolymer for use in the production of articles which contact the blood. The copolymer contains quaternary ammonium groups to which the heparin coating binds. U.S. Pat. No. 5,391,580 proposes a poly(sulfone-alpha-olefin) composite article for use in blood oxygenation. The article includes a polypropylene tube, and a polysulfone perm-selective homogeneous layer directly adhered to the polypropylene tube. Heparin is covalently linked to the polysulfone perm-selective layer.
There remains a need in the art for heparin coating compositions which can be applied to blood-contacting surfaces of medical devices. There further remains a need in the art for heparin coating compositions which do not lose their anti-thrombogenic effects over time. There remains a need in the art for heparin coating compositions which can be produced in a cost-effective and commercially feasible manner and which can be applied to blood-contacting surfaces of medical devices in a commercially feasible manner.